The cardiac glycosides and the sympathomimetic amines are the principal inotropic agents used in the management of congestive heart failure. Although the cardiac glycosides, especially digitalis, are among the most frequently prescribed drugs, they have numerous liabilities such as a low therapeutic index and erratic absorption, and are associated with life-threatening arrhythmias and deleterious drug-drug interactions. In addition, many patients either do not respond, or become refractory to these agents. The sympathomimetic amines, such as dopamine and epinephrine, have limited utility due to positive chronotropic effects, arrhythmogenic properties, and oral ineffectiveness.
More recently, new classes of inotropic agents have been found. Among these, certain 2-phenylimidazo-[4,5-b]pyridines (U.S. Pat. Nos. 3,985,891 and 4,327,100) have been shown to possess inotropic and anticoagulant activity. U.S. Pat. Nos. 4,299,834 and 4,353,909 describe similarly substituted purine and 6-hydroxy-imidazo[4,5-b]pyridine derivatives. The analogous imidazo[4,5-c]pyridines have also been taught to be inotropic agents. See, e.g., European Patent Application Nos. 72,926 and 79,083 and British Patent Application No. 2,119,377.
Certain 3-alkyl-2-phenylimidazo[1,2-a]pyrimidines are taught in French Pat. No. 2,510,576 to be anti-inflammatory agents. Certain imidazo-pyridines and -pyrazines and their 5,6,7,8-tetrahydro analogs are taught to be anti-secretory agents in European Patent Application Nos. 33,094 and 68,378. 2-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine is taught in J. Chem. Soc. (C), 3280 (1971); no pharmaceutical utility is disclosed.
The present invention provides for a series of novel phenylimidazole compounds, their formulations and their use as orally effective positive inotropic agents which have minimal effects on blood pressure and heart rate. The compounds also possess vasodilitation activity.